Search

Background/Objectives: This study aims to broaden the knowledge on co-amorphous phospholipid systems (CAPSs) by exploring the formation of CAPSs with a broader range of poorly water-soluble drugs, celecoxib (CCX), furosemide (FUR), nilotinib (NIL), and ritonavir (RIT), combined with amphiphilic phospholipids (PLs), including soybean phosphatidylcholine (SPC), hydrogenated phosphatidylcholine (HPC), and mono-acyl phosphatidylcholine (MAPC). Methods: The CAPSs were initially prepared at equimolar drug-to-phospholipid (PL) ratios by mechano-chemical activation-based, melt-based, and solvent-based preparation methods, i.e., ball milling (BM), quench cooling (QC), and solvent evaporation (SE), respectively. The solid state of the product was characterized by X-ray powder diffraction (XRPD), polarized light microscopy (PLM), and differential scanning calorimetry (DSC). The long-term physical stability of the CAPSs was investigated at room temperature under dry conditions (0% RH) and at 75% RH. The dissolution behavior of the CCX CAPS and RIT CAPS was studied. Results: Our findings indicate that SE consistently prepared CAPSs for CCX-PLs, FUR-PLs, and RIT-PLs, whereas the QC method could only form CAPSs for RIT-PLs, CCX-SPC, and CCX-MAPC. In contrast, the BM method failed to produce CAPSs, but all drugs alone could be fully amorphized. While the stability of each drug varied depending on the PLs used, the SE CAPS consistently demonstrated the highest stability by a significant margin. Initially, a 1:1 molar ratio was used for screening all systems, though the optimal molar ratio for drug stability remained uncertain. To address this, various molar ratios were investigated to determine the ratio yielding the highest amorphous drug stability. Our results indicate that all systems remained physically stable at a 1.5:1 ratio and with excess of PL. Furthermore, the CAPS formed by the SE significantly improves the dissolution behavior of CCX and RIT, whereas the PLs provide a slight precipitation inhibition for supersaturated CCX and RIT. Conclusions: These findings support the use of a 1:1 molar ratio in screening processes and suggest that CAPSs can be effectively prepared with relatively high drug loads compared to traditional drug–polymer systems. Furthermore, the study highlights the critical role of drug selection, the preparation method, and the PL type in developing stable and effective CAPSs. [ABSTRACT FROM AUTHOR]

Nanocomposites represent one of the most useful strategies for resolving the pharmaceutical challenge about the dissolution and delivery of poorly water-soluble drugs. Besides the compatibility between the drug and polymeric carriers, the physical shapes of materials also play their important roles on the release behaviors of a guest poorly water-soluble drug from the host polymeric matrices. In this study, three kinds of nanocomposites in the forms of homogeneous nanofibers (E1), spindles-on-a-string (E2), and beads-on-a-string (E3) were prepared using electrospinning with ketoprofen (KET) as the model drug and a mixture of ethylcellulose (EC) and polyvinylpyrrolidone (PVP) as the polymeric matrices. Controllable preparation mechanisms of these morphologies are disclosed based on the results of SEM, TEM, and processes observations. XRD and FTIR data demonstrated that KET was compatible with PVP and EC. In vitro dissolution tests verified that all the three nanocomposites were able to provide the typical bi-stage fast-sustained release profiles of KET. Whereas, the beads-on-a-string E3 had a better functional performance than the spindles-on-a-string E2, and the homogeneous nanofibers E1 in terms of the KET sustained release profiles in the second stage. The protocols reported here pioneered a new way for developing novel functional nanocomposites based on the process-shape-performance relationship. [ABSTRACT FROM AUTHOR]

Nanocomposites represent one of the most useful strategies for resolving the pharmaceutical challenge about the dissolution and delivery of poorly water-soluble drugs. Besides the compatibility between the drug and polymeric carriers, the physical shapes of materials also play their important roles on the release behaviors of a guest poorly water-soluble drug from the host polymeric matrices. In this study, three kinds of nanocomposites in the forms of homogeneous nanofibers (E1), spindles-on-a-string (E2), and beads-on-a-string (E3) were prepared using electrospinning with ketoprofen (KET) as the model drug and a mixture of ethylcellulose (EC) and polyvinylpyrrolidone (PVP) as the polymeric matrices. Controllable preparation mechanisms of these morphologies are disclosed based on the results of SEM, TEM, and processes observations. XRD and FTIR data demonstrated that KET was compatible with PVP and EC. In vitro dissolution tests verified that all the three nanocomposites were able to provide the typical bi-stage fast-sustained release profiles of KET. Whereas, the beads-on-a-string E3 had a better functional performance than the spindles-on-a-string E2, and the homogeneous nanofibers E1 in terms of the KET sustained release profiles in the second stage. The protocols reported here pioneered a new way for developing novel functional nanocomposites based on the process-shape-performance relationship.

About 40% of approved drugs and nearly 90% of drug candidates are poorly water-soluble drugs. Low solubility reduces the drugability. Effectively improving the solubility and bioavailability of poorly water-soluble drugs is a critical issue that needs to be urgently addressed in drug development and application. This review briefly introduces the conventional solubilization techniques such as solubilizers, hydrotropes, cosolvents, prodrugs, salt modification, micronization, cyclodextrin inclusion, solid dispersions, and details the crystallization strategies, ionic liquids, and polymer-based, lipid-based, and inorganic-based carriers in improving solubility and bioavailability. Some of the most commonly used approved carrier materials for solubilization techniques are presented. Several approved poorly water-soluble drugs using solubilization techniques are summarized. Furthermore, this review summarizes the solubilization mechanism of each solubilization technique, reviews the latest research advances and challenges, and evaluates the potential for clinical translation. This review could guide the selection of a solubilization approach, dosage form, and administration route for poorly water-soluble drugs. Moreover, we discuss several promising solubilization techniques attracting increasing attention worldwide. This review intends to summarize the solubilization techniques used for poorly water-soluble drugs, with a view to providing guidance to researchers to select solubilization techniques. [Display omitted] [ABSTRACT FROM AUTHOR]

Core–shell nanostructures are powerful platforms for the development of novel nanoscale drug delivery systems with sustained drug release profiles. Coaxial electrospinning is facile and convenient for creating medicated core–shell nanostructures with elaborate designs with which the sustained-release behaviors of drug molecules can be intentionally adjusted. With resveratrol (RES) as a model for a poorly water-soluble drug and cellulose acetate (CA) and PVP as polymeric carriers, a brand-new electrospun core–shell nanostructure was fabricated in this study. The guest RES and the host CA molecules were designed to have a reverse gradient distribution within the core–shell nanostructures. Scanning electron microscope and transmission electron microscope evaluations verified that these nanofibers had linear morphologies, without beads or spindles, and an obvious core–shell double-chamber structure. The X-ray diffraction patterns and Fourier transform infrared spectroscopic results indicated that the involved components were highly compatible and presented in an amorphous molecular distribution state. In vitro dissolution tests verified that the new core–shell structures were able to prevent the initial burst release, extend the continuous-release time period, and reduce the negative tailing-off release effect, thus ensuring a better sustained-release profile than the traditional blended drug-loaded nanofibers. The mechanism underlying the influence of the new core–shell structure with an RES/CA reverse gradient distribution on the behaviors of RES release is proposed. Based on this proof-of-concept demonstration, a series of advanced functional nanomaterials can be similarly developed based on the gradient distributions of functional molecules within electrospun multi-chamber nanostructures. [ABSTRACT FROM AUTHOR]

Increasing influx of poorly water-soluble drugs poses a significant challenge to oral drug delivery. Conventional solubilization techniques such as solid dispersion and cyclodextrin inclusion, while capable of improving drug dissolution, suffer from a great predicament in subsequent formulation processing. A novel “powder solution technology,” the liquisolid technique, has come to the forefront in dealing with drug solubilization and formulation of oral “problem” drugs. The liquisolid technique involves the adsorption of liquid medications onto suitable carrier and coating materials, followed by conversion into free-flowing, dry-looking, and compressible powders. In the liquisolid system, the drug is dispersed in an almost molecular state, which greatly contributes to drug dissolution and absorption. This review aims to present the fundamentals of liquisolid technology and update the concept of liquisolid processing to expand its applications. The trend of modern drug discovery, drug solubilization approaches, application of liquisolid technology in formulation innovation, formulation composition, and design of liquisolid systems were discussed in detail. Special emphasis was placed on the application of liquisolid technology to improve the dissolution and bioavailability of poorly water-soluble drugs. Accumulating evidence shows that the liquisolid technology has immense potential to improve oral delivery and facilitate the secondary development of insoluble drugs.

In this study, three kinds of electrohydrodynamic atomization (EHDA) processes (electrospraying, electrospinning, and coaxial electrospinning) are implemented to create hydroxypropyl methylcellulose (HPMC) based ultra‐thin products for providing the fast dissolution of a poorly water‐soluble drug ketoprofen (KET). An EHDA apparatus, characterized by a novel spinneret, is homemade for conducting the three processes. The three types of products are electrospun nanofibers E1, electrosprayed microparticles E2, and core‐shell nanofibers E3. SEM and TEM results indicate that they have the anticipated morphologies and inner structures. X‐ray diffraction and Fourier Transform Infrared results verify that KET is mainly amorphous in all the composites due to its fine compatibility with HPMC. In vitro dissolution tests demonstrate that the drug rapid release performances has an order of E3>E1>E2≫KET powders. The fast dissolution mechanisms are suggested and the advantages of the three products are compared. The super performance of E3 in furnishing the rapid release is attributed to a synergistic action of small size (of the shell thickness), high porosity, amorphous state of drug, and the solubility of HPMC. EHDA nanostructures can support the development of nano drug delivery systems (DDSs) through tailoring the spatial distribution of drug molecules within the nano products. [ABSTRACT FROM AUTHOR]

The aim of this study was to determine the drug loading capacity of phosphatidylcholine-based formulations for four poorly water-soluble drug substances (clofazimine, fenofibrate, artemether, cannabidiol). Two self-dispersing lipid formulations were investigated, which consisted of soybean phospholipids, medium-chain triglycerides and ethanol with a different phospholipid–oil ratio. The direct loading of the bulk formulation was conducted with dual centrifugation, which proved to be a suitable method for screening experiments with the highly viscous formulations. To estimate possible precipitation after dispersion in the gastrointestinal fluids, the solubility of the drugs was investigated in the dispersed formulations. For this purpose, nanodispersions were prepared from the bulk formulations via high pressure homogenization and subsequently subjected to passive loading. A newly developed HPLC method with Charged Aerosol Detection allowed a simultaneous evaluation of the content of soybean lecithin and medium-chain triglycerides in the nanodispersions. When comparing the two phosphatidylcholine-based formulations, a high content of oil was advantageous with regard to a high loading capacity. Drug substances with melting points below 150 °C exhibited a high solubility in the phospholipid-based formulations. A surprisingly high solubility was observed for artemether and cannabidiol with up to 13.0% and 33.3% drug loaded to the formulations, respectively. In the dispersions, a similar solubility as in the bulk formulations was obtained for fenofibrate and cannabidiol. Clofazimine yielded a higher loading result in the nanodispersions than in the bulk formulation. [ABSTRACT FROM AUTHOR]

In this study, bile acid-based vesicles and nanoparticles (i.e., bilosomes and biloparticles) are studied to improve the water solubility of lipophilic drugs. Ursodeoxycholic acid, sodium cholate, sodium taurocholate and budesonide were used as bile acids and model drugs, respectively. Bilosomes and biloparticles were prepared following standard protocols with minor changes, after a preformulation study. The obtained systems showed good encapsulation efficiency and dimensional stability. Particularly, for biloparticles, the increase in encapsulation efficiency followed the order ursodeoxycholic acid < sodium cholate < sodium taurocholate. The in vitro release of budesonide from both bilosytems was performed by means of dialysis using either a nylon membrane or a portion of Wistar rat small intestine and two receiving solutions (i.e., simulated gastric and intestinal fluids). Both in gastric and intestinal fluid, budesonide was released from bilosystems more slowly than the reference solution, while biloparticles showed a significant improvement in the passage of budesonide into aqueous solution. Immunofluorescence experiments indicated that ursodeoxycholic acid bilosomes containing budesonide are effective in reducing the inflammatory response induced by glucose oxidase stimuli and counteract ox-inflammatory damage within intestinal cells. [ABSTRACT FROM AUTHOR]

Cellulose beads emerge as carriers for poorly water-soluble drugs due to their eco-friendly raw materials and favorable porous structure. However, drug dissolution may be limited by their poor swelling ability and the presence of closed pores caused by shrinkage of the pristine cellulose beads. In this study, novel cellulose beads that can swell in acidic environment were prepared by introducing ethylenediamine (EDA) on dialdehyde cellulose (DAC), thereby addressing the shrinkage and closed pore problem of cellulose beads. The effect of the ratio of EDA on the swelling behavior and amine content of beads was studied. Three model drugs with different physicochemical properties were selected to study the physical state of loaded drugs and their release behavior. According to the results of XRPD and DSC, indomethacin and itraconazole loaded in the beads were amorphous at a drug loading of 20%, but fenofibrate was partially crystalline. Both bead size and the ratio of amine groups influenced the release behavior of the model drugs. The in vitro dissolution results showed that the cationic beads greatly improved the solubility and dissolution rate of the drug compared with the crystalline drug. Beads with a small size and high ratio of EDA tend to achieve a better drug dissolution rate and cumulative release percentage. Physical stability studies of the itraconazole-loaded beads were also implemented under four different temperature/humidity conditions for up to two months. The results showed that crystallization only appeared after two months of storage at 40°/75% RH, and the drug maintained a non-crystalline state in the other three storage conditions (0 °C/0 %RH, 0 °C/32 %RH, 25 °C/32 %RH). In conclusion, the novel pH-responsive cationic cellulose beads show great potential as a carrier for improving the rate and extent of dissolution of poorly soluble drugs and maintaining supersaturation.

The toxicity of local anesthetics is a serious problem, given their widespread use. One of the main causes of the side effects of local anesthetics is their non-selectivity of action in the body. A possible way to increase the selectivity of the action of drugs is to use the photopharmacology approach. Previously, we described the light-controlled local anesthetic ethercaine, the biological effect of which can be controlled using light, thereby increasing its selectivity of action. An important limitation of ethercaine was its low solubility in water, limiting the potential of this compound. In this work, we developed a dosage form of ethercaine, which allowed us to increase its solubility from 0.6% to 2% or more. The resulting 1% solution of ethercaine hydrochloride in 4% Kolliphor ELP had high biological activity on the surface anesthesia model, while demonstrating low acute toxicity in mice with intravenous administration (4–5 times less than that of lidocaine). [ABSTRACT FROM AUTHOR]

The prevalence of active pharmaceutical ingredients (APIs) with low water solubility has experienced a significant increase in recent years. These APIs present challenges in formulation, particularly for oral dosage forms, despite their considerable therapeutic potential. Therefore, the improvement of solubility has become a major concern for pharmaceutical enterprises to increase the bioavailability of APIs. A promising formulation approach that can effectively improve the dissolution profile and the bioavailability of poorly water-soluble drugs is the utilization of amorphous systems. Numerous formulation methods have been developed to enhance poorly water-soluble drugs through amorphization systems, including co-amorphous formulations, amorphous solid dispersions (ASDs), and the use of mesoporous silica as a carrier. Furthermore, the successful enhancement of certain drugs with poor aqueous solubility through amorphization has led to their incorporation into various commercially available preparations, such as ASDs, where the crystalline structure of APIs is transformed into an amorphous state within a hydrophilic matrix. A novel approach, known as ternary solid dispersions (TSDs), has emerged to address the solubility and bioavailability challenges associated with amorphous drugs. Meanwhile, the introduction of a third component in the ASD and co-amorphous systems has demonstrated the potential to improve performance in terms of solubility, physical stability, and processability. This comprehensive review discusses the preparation and characterization of poorly water-soluble drugs in ternary solid dispersions and their mechanisms of drug release and physical stability. [ABSTRACT FROM AUTHOR]

Drug solubility limits intravenous dosing for poorly water-soluble medicines, which misrepresents their bioavailability estimation. The current study explored a method using a stable isotope tracer to assess the bioavailability of drugs that are poorly water-soluble. HGR4113 and its deuterated analog, HGR4113-d7, were tested as model drugs. To determine the level of HGR4113 and HGR4113-d7 in rat plasma, a bioanalytical method using LC-MS/MS was developed. The HGR4113-d7 was intravenously administered to rats that were orally pre-administered HGR4113 at different doses; subsequently, the plasma samples were collected. HGR4113 and HGR4113-d7 were simultaneously determined in the plasma samples, and bioavailability was calculated using plasma drug concentration values. The bioavailability of HGR4113 was 53.3% ± 19.5%, 56.9% ± 14.0%, and 67.8% ± 16.7% after oral dosages of 40, 80, and 160 mg/kg, respectively. By eliminating the differences in clearance between intravenous and oral dosages at different levels, acquired data showed that the current method reduced measurement errors in bioavailability when compared to the conventional approach. The present study suggests a prominent method for evaluating the bioavailability of drugs with poor aqueous solubility in preclinical studies. [ABSTRACT FROM AUTHOR]

A high percentage of marketed drugs suffer from poor water solubility and require an appropriate technique to increase their solubility. This study aims to compare physically modified and unmodified gum polymers extracted from Ziziphus spina-christi fruits as solid dispersion carriers for some drugs. Taguchi Orthogonal Design (L9) was chosen for the screening and optimization of the solid dispersions. The design has four factors: type of drug, type of polymer, type of solid dispersion process, and drug to polymer ratio. Each factor was varied in three stages and the total number of runs was 9 in triplicate. The polymer was physically modified by heating (M1ZG) or freeze-drying (M2ZG). The drugs were selected according to the biopharmaceutical classification system, namely loratadine and glimepiride (class II) and furosemide (class IV). Drugs were dispersed in the polymer in three different ratios 1: 1, 1: 2, and 1: 3. Solid dispersions were made by co-grinding, solvent evaporation, and kneading methods. Modified and unmodified polymers were characterized in terms of their organoleptic properties, solubility, powder flowability, density, viscosity, swelling index, and water retention capacity. Solid dispersions were characterized in terms of percentage practical yield, solubility improvement, and drug compatibility. The results showed that the organoleptic properties of polymers were not changed by the gum modification. The swelling index of the polymer was doubled in M1ZG. The viscosity and water retention capacity of the polymer was increased in both modified polymers. All solid dispersions showed a high practical percentage yield of more than 93%, the higher values ​​being more associated with loratadine and furosemide than with glimepiride. The improvement in solubility was observed in all solid dispersions prepared, the values ​​varying with the pH of the medium and the method of modification. The FTIR results indicated that there was no chemical interaction between these drugs and the polymer used. Analysis of the results according to the Taguchi orthogonal design indicated 51 folds aqueous solubility enhancement for loratadine using M2ZG polymer at a ratio of 1: 3 of Drug: polymer. This study showed the possibility of improving the solubility of other poorly soluble drugs.

Abstract Chagas disease is a neglected parasitic disease caused by Trypanosoma cruzi, whose treatment has remained unsatisfactory for over 50 years, given that it is limited to two drugs. Benznidazole (BZN) is an efficient antichagasic drug used as the first choice, although its poor water-solubility, irregular oral absorption, low efficacy in the chronic phase, and various associated adverse effects are limiting factors for treatment. Incorporating drugs with such characteristics into nanostructured lipid carriers (NLC) is a promising alternative to overcome these limiting obstacles, enhancing drug efficacy and bioavailability while reducing toxicity. Therefore, this study proposed NLC-BZN formulations in different compositions prepared by hot-melt homogenization followed by ultrasound, and the optimized formulation was characterized by FTIR, DRX, DSC, and thermogravimetry. Biological activities included in vitro membrane toxicity (red blood cells), fibroblast cell cytotoxicity, and trypanocidal activity against epimastigotes of the Colombian strain of T. cruzi. The optimized NLC-BZN had a small size (110 nm), negative zeta potential (-18.0 mV), and high encapsulation (1.64% of drug loading), as shown by infrared spectroscopy, X-ray diffraction, and thermal analysis. The NLC-BZN also promoted lower in vitro membrane toxicity (

The biopharmaceutical classification system groups low-solubility drugs into two groups: II and IV, with high and low permeability, respectively. Most of the new drugs developed for common pathologies present solubility issues. This is the case of lurasidone hydrochloride—a drug used for the treatment of schizophrenia and bipolar depression. Likewise, the stability problems of some drugs limit the possibility of preparing them in liquid pharmaceutical forms where hydrolysis and oxidation reactions can be favored. Lurasidone hydrochloride presents the isoindole-1,3-dione ring, which is highly susceptible to alkaline hydrolysis, and the benzisothiazole ring, which is susceptible to a lesser extent to oxidation. Herein, we propose to study the increase in the solubility and stability of lurasidone hydrochloride by the formation of higher-order inclusion complexes with hydroxypropyl-β-cyclodextrin. Several stoichiometric relationships were studied at between 0.5 and 3 hydroxypropyl-β-cyclodextrin molecules per drug molecule. The obtained products were characterized, and their solubility and stability were assessed. According to the obtained results, the formation of inclusion complexes dramatically increased the solubility of the drug, and this increased with the increase in the inclusion ratio. This was associated with the loss of crystalline state of the drug, which was in an amorphous state according to infrared spectroscopy, calorimetry, and X-ray analysis. This was also correlated with the stabilization of lurasidone by the cyclodextrin inhibiting its recrystallization. Phase solubility,1H-NMR, and docking computational characterization suggested that the main stoichiometric ratio was 1:1; however, we cannot rule out a 1:2 ratio, where a second cyclodextrin molecule could bind through the isoindole-1,3-dione ring, improving its stability as well. Finally, we can conclude that the formation of higher-order inclusion complexes of lurasidone with hydroxypropyl-β-cyclodextrin is a successful strategy to increase the solubility and stability of the drug. [ABSTRACT FROM AUTHOR]

In non-strongly interacting co-amorphous systems, addition of a polymer, to further stabilize the co-amorphous systems, may influence the phase behavior between the components. In this study, the evolution of the composition of the amorphous phase in the ternary system carvedilol (CAR)-tryptophan (TRP)-hydroxypropylmethyl cellulose (HPMC) was investigated, based upon previously formed and characterized binary systems to which the third component was added (CAR − TRP + HPMC, CAR − HPMC + TRP and TRP − HPMC + CAR). Ball milling was used as the preparation method for all binary and ternary systems. The influence of the milling time on the co-amorphous systems was monitored by DSC and XRPD. Addition of HPMC reduced the miscibility of CAR with TRP due to hydrogen bond formation between CAR and polymer. These bonds became dominant for the interaction pattern. In addition, when CAR or TRP exceeded the miscibility limit in HPMC, phase separation and eventually crystallization of CAR and TRP was observed. All ternary co-amorphous systems eventually reached the same composition, albeit following different paths depending on the initially used binary system. [ABSTRACT FROM AUTHOR]

The poor bioavailability of many newly developed active pharmaceutical ingredients (APIs) poses a major challenge in formulation development. To overcome this issue, strategies such as the preparation of amorphous solid dispersions (ASDs), and the application of the APIs in lipid nanocarriers or the wet-milling of the substances into nanoparticles have been introduced. In addition to an efficient formulation strategy, a dosage form that is accepted by all patients is also of great importance. To enable a simple application of the oral dosage form for all patients, orodispersible films (ODFs) are a very promising delivery platform for the APIs because the films directly disintegrate in the mouth. In this study, two poorly water-soluble APIs, fenofibrate and naproxen, were formulated using five different formulation strategies and then embedded in ODFs. It was found that the deliverable amount of API with one ODF highly depends on the formulation strategy as well as the physicochemical properties of the formulated API. The most promising film formulations were ASD-ODFs as well as films with API-loaded lipid nanoemulsions. Both showed a reduction of the dissolution time of the APIs from the ODF compared to an ODF with unformulated API micro particles. In addition, short disintegration times were achieved, although the mechanical film properties were slightly worse compared to the API-free film formulation. [ABSTRACT FROM AUTHOR]

Mirtazapine is a tetracyclic anti-depressant with poor water solubility. The aim of this study was to improve the dissolution rate of mirtazapine by delivering the drug as a liquisolid compact. Central composite design (CCD) was employed for the preparation of mirtazapine liquisolid compacts. In this, the impacts of two independent factors, i.e., excipient ratio (carrier:coating) and different drug concentration on the response of liquisolid system were optimized. Liquisolid compacts were prepared using propylene glycol as a solvent, microcrystalline cellulose as a carrier, and silicon dioxide (Aerosil) as the coating material. The crystallinity of the formulated drug and the interactions between the excipients were examined using X-ray powder diffraction (XRD) and Fourier-transform infrared spectroscopy (FTIR), respectively. The dissolution study for the liquisolid compact was carried out as per FDA guidelines. The results showed loss of crystallinity of the mirtazapine in the formulation and was completely solubilized in non-volatile solvent and equally dispersed throughout the powder system. Moreover, drug dissolution was found to be higher in liquisolid compacts than the direct compressed conventional tablets (of mirtazapine). The liquisolid technique appears to be a promising approach for improving the dissolution of poorly soluble drugs like mirtazapine. [ABSTRACT FROM AUTHOR]

A high percentage of marketed drugs suffer from poor water solubility and require an appropriate technique to increase their solubility. This study aims to compare physically modified and unmodified gum polymers extracted from Ziziphus spina-christi fruits as solid dispersion carriers for some drugs. Taguchi Orthogonal Design (L9) was chosen for the screening and optimization of the solid dispersions. The design has four factors: type of drug, type of polymer, type of solid dispersion process, and drug to polymer ratio. Each factor was varied in three stages and the total number of runs was 9 in triplicate. The polymer was physically modified by heating (M1ZG) or freeze-drying (M2ZG). The drugs were selected according to the biopharmaceutical classification system, namely loratadine and glimepiride (class II) and furosemide (class IV). Drugs were dispersed in the polymer in three different ratios 1: 1, 1: 2, and 1: 3. Solid dispersions were made by co-grinding, solvent evaporation, and kneading methods. Modified and unmodified polymers were characterized in terms of their organoleptic properties, solubility, powder flowability, density, viscosity, swelling index, and water retention capacity. Solid dispersions were characterized in terms of percentage practical yield, solubility improvement, and drug compatibility. The results showed that the organoleptic properties of polymers were not changed by the gum modification. The swelling index of the polymer was doubled in M1ZG. The viscosity and water retention capacity of the polymer was increased in both modified polymers. All solid dispersions showed a high practical percentage yield of more than 93%, the higher values ​​being more associated with loratadine and furosemide than with glimepiride. The improvement in solubility was observed in all solid dispersions prepared, the values ​​varying with the pH of the medium and the method of modification. The FTIR results indicated that there was no chemical interaction between these drugs and the polymer used. Analysis of the results according to the Taguchi orthogonal design indicated 51 folds aqueous solubility enhancement for loratadine using M2ZG polymer at a ratio of 1: 3 of Drug: polymer. This study showed the possibility of improving the solubility of other poorly soluble drugs. [ABSTRACT FROM AUTHOR]

Amorphous solid dispersions (ASDs) can increase the oral bioavailability of poorly soluble drugs. However, their use in drug development is comparably rare due to a lack of basic understanding of mechanisms governing drug liberation and absorption in vivo. Furthermore, the lack of a unified nomenclature hampers the interpretation and classification of research data. In this review, we therefore summarize and conceptualize mechanisms covering the dissolution of ASDs, formation of supersaturated ASD solutions, factors responsible for solution stabilization, drug uptake from ASD solutions, and drug distribution within these complex systems as well as effects of excipients. Furthermore, we discuss the importance of these findings on the development of ASDs. This improved overall understanding of these mechanisms will facilitate a rational ASD formulation development and will serve as a basis for further mechanistic research on drug delivery by ASDs.

The purpose of the present study was to harmonize the protocol of equilibrium solubility measurements for poorly water-soluble drugs to lower inter-laboratory variance. The “mandatory” and “recommended” procedures for the shake-flask method were harmonized based on the knowledge and experiences of each company and information from the literature. The solubility of model drugs was measured by the harmonized protocol (HP) and the non-harmonized proprietary protocol of each company (nonHP). Albendazole, griseofulvin, dipyridamole, and glibenclamide were used as model drugs. When using the nonHP, the solubility values showed large inter-laboratory variance. In contrast, inter-laboratory variance was markedly reduced when using the HP.

Amorphous solid dispersions (ASDs) can increase the oral bioavailability of poorly soluble drugs. However, their use in drug development is comparably rare due to a lack of basic understanding of mechanisms governing drug liberation and absorption in vivo. Furthermore, the lack of a unified nomenclature hampers the interpretation and classification of research data. In this review, we therefore summarize and conceptualize mechanisms covering the dissolution of ASDs, formation of supersaturated ASD solutions, factors responsible for solution stabilization, drug uptake from ASD solutions, and drug distribution within these complex systems as well as effects of excipients. Furthermore, we discuss the importance of these findings on the development of ASDs. This improved overall understanding of these mechanisms will facilitate a rational ASD formulation development and will serve as a basis for further mechanistic research on drug delivery by ASDs. [ABSTRACT FROM AUTHOR]

Cancer is one of the leading causes of death worldwide. In the available treatments, chemotherapy is one of the most used, but has several associated problems, namely the high toxicity to normal cells and the resistance acquired by cancer cells to the therapeutic agents. The scientific community has been battling against this disease, developing new strategies and new potential chemotherapeutic agents. However, new drugs often exhibit poor solubility in water, which led researchers to develop functionalized nanosystems to carry and, specifically deliver, the drugs to cancer cells, targeting overexpressed receptors, proteins, and organelles. Thus, this review is focused on the recent developments of functionalized nanosystems used to carry poorly water-soluble drugs, with special emphasis on liposomes and albumin-based nanosystems, two major classes of organic nanocarriers with formulations already approved by the U.S. Food and Drug Administration (FDA) for cancer therapeutics.

Self-emulsifying drug delivery systems (SEDDS) can improve the oral bioavailability of poorly water-soluble drugs. Solid self-emulsifying drug delivery systems (s-SEDDS) offer several advantages including improved drug stability, ease of administration, and production. Most compounds employed in developing s-SEDDS are solid in nature, with a high amount of surfactants added. The aim of this study was to develop an s-SEDDS using a tocotrienol-rich fraction (TRF) as the model liquid active substance via a simple adsorption method. The solid formulation was developed using magnesium aluminosilicate as the carrier with 70% TRF and 30% surfactants (poloxamer and Labrasol®). The formulation showed good self-emulsification efficiency with stable emulsion formed, excellent powder flowability, and small emulsion droplet size of 210–277 nm. The s-SEDDS with combined surfactants (poloxamer and Labrasol®) showed a faster absorption rate compared to preparations with only a single surfactant and enhanced oral bioavailability (3.4–3.8 times higher) compared to the non-self-emulsifying oily preparation when administered at a fasted state in rats. In conclusion, an s-SEDDS containing a high amount of TRF was successfully developed. It may serve as a useful alternative to a liquid product with enhanced oral bioavailability and the added advantage of being a solid dosage form.

Most of the newly developed drug candidates are lipophilic and poorly water-soluble. Enhancing the dissolution and bioavailability of these drugs is a major challenge for the pharmaceutical industry. Liquisolid technique, which is based on the conversion of the drug in liquid state into an apparently dry, non-adherent, free flowing and compressible powder, is a novel and advanced approach to tackle the issue. The objective of this article is to present an overview of liquisolid technique and summarize the progress of its applications in pharmaceutics. Low cost, simple processing and great potentials in industrial production are main advantages of this approach. In addition to the enhancement of dissolution rate of poorly water-soluble drugs, this technique is also a fairly new technique to effectively retard drug release. Furthermore, liquisolid technique has been investigated as a tool to minimize the effect of pH variation on drug release and as a promising alternative to conventional coating for the improvement of drug photostability in solid dosage forms. Overall, liquisolid technique is a newly developed and promising tool for enhancing drug dissolution and sustaining drug release, and its potential applications in pharmaceutics are still being broadened.

This study examined the impact of stirrer speed and bead material loading on fenofibrate particle breakage during wet stirred media milling (WSMM) via three kinetic models and a microhydrodynamic model. Evolution of median particle size was tracked via laser diffraction during WSMM operating at 3000–4000 rpm with 35–50% (v/v) concentration of polystyrene or zirconia beads. Additional experiments were performed at the center points of the above conditions, as well as outside the range of these conditions, in order to test the predictive capability of the models. First-order, nth-order, and warped-time kinetic models were fitted to the data. Main effects plots helped to visualize the influence of the milling variables on the breakage kinetics and microhydrodynamic parameters. A subset selection algorithm was used along with a multiple linear regression model (MLRM) to delineate how the breakage rate constant k was affected by the microhydrodynamic parameters. As a comparison, a purely empirical correlation for k was also developed in terms of the process/bead parameters. The nth-order model was found to be the best model to describe the temporal evolution; nearly second-order kinetics (n ≅ 2) was observed. When the process was operated at a higher stirrer speed and/or higher loading with zirconia beads as opposed to polystyrene beads, the breakage occurred faster. A statistically significant (p-value ≤ 0.01) MLRM of three microhydrodynamic parameters explained the variation in the breakage rate constant best (R2 ≥ 0.99). Not only do the models and the nth-order kinetic–microhydrodynamic correlation enable deeper process understanding toward developing a WSMM process with reduced cycle time, but they also provide good predictive capability, while outperforming the purely empirical correlation.

The number of poorly soluble new drugs is increasing and one of the effective ways to deliver such pharmaceutically active molecules is using hydrophilic polymers to form a solid dispersion. Bile salts play an important role in the solubilisation of poorly soluble compounds in the gastrointestinal tract (gut) prior to absorption. When a poorly water-soluble drug is delivered using a hydrophilic polymer based solid dispersion oral formulation, it is still unclear whether there are any polymer-bile salt interactions, which may influence the drug dissolution and solubilisation. This study, using two widely used hydrophilic model polymers, Hydroxypropyl methylcellulose (HPMC) and polyvynilpirrolidone (PVP), and sodium taurocholate (NaTC) as the model bile salt, aims to investigate the interactions between the polymers and bile salts in simulated fed state (FeSSIF) and fasted state (FaSSIF) gut fluids. The nature of the interactions was characterised using a range of NMR techniques. The results revealed that the aggregation behaviour of NaTC in FaSSIF and FeSSIF is much more complex than in water. The addition of hydrophilic polymers led to the occurrences of NaTC-HPMC and NaTC-PVP aggregation. For both systems, pH and ionic strength strongly influenced the aggregation behavior, while the ion type played a less significant role. The outcome of this study enriched the understanding of the aggregation behaviour of bile salts and typical hydrophilic pharmaceutical polymers in bio-relevant media. Due to the high surface-activity of the bile salts and their ability to interact with polymers, such aggregation behaviour is expected to play a role in drug solubilisation in the gut when the drug is delivered by hydrophilic polymer based dispersions. [ABSTRACT FROM AUTHOR]

• Physical stability of BLG-stabilized ASD was evaluated for five drugs. • Ketoconazole and rifaximin remained stable at 90 % loading for 12 months. • Stabilization mechanisms: steric confinement, hydrogen bonds, and others. • Crystal-patterned cluster search was introduced in molecular dynamics simulations. • In silico approach proved promising for prediction of long-term stability of ASDs. Our previous work shows that β-lactoglobulin-stabilized amorphous solid dispersion (ASD) loaded with 70 % indomethacin remains stable for more than 12 months. The stability is probably due to hydrogen bond networks spread throughout the ASD, facilitated by the indomethacin which has both hydrogen donors and acceptors. To investigate the stabilization mechanisms further, here we tested five other drug molecules, including two without any hydrogen bond donors. A combination of experimental techniques (differential scanning calorimetry, X-ray power diffraction) and molecular dynamics simulations was used to find the maximum drug loadings for ASDs with furosemide, griseofulvin, ibuprofen, ketoconazole and rifaximin. This approach revealed the underlying stabilization factors and the capacity of computer simulations to predict ASD stability. We searched the ASD models for crystalline patterns, and analyzed diffusivity of the drug molecules and hydrogen bond formation. ASDs loaded with rifaximin and ketoconazole remained stable for at least 12 months, even at 90 % drug loading, whereas stable drug loadings for furosemide, griseofulvin and ibuprofen were at a maximum of 70, 50 and 40 %, respectively. Steric confinement and hydrogen bonding to the proteins were the most important stabilization mechanisms at low drug loadings (≤ 40 %). Inter-drug hydrogen bond networks (including those with induced donors), ionic interactions, and a high T g of the drug molecule were additional factors stabilizing the ASDs at drug loading greater than 40 %. [Display omitted] [ABSTRACT FROM AUTHOR]

The main objective of this study was to develop a pH gradient release pellet with self-emulsifying drug delivery system (SEDDS), which could not only improve the oral bioavailability of Vinpocetine (VIN), a poor soluble drug, but reduce the fluctuation of plasma concentration. First, the liquid VIN SEDDS formulation was prepared. Then the self-emulsifying pH gradient release pellets were prepared by extrusion spheronization technique, and formulation consisted by the liquid SEDDS, absorbent (colloidal silicon dioxide), penetration enhancer (sodium chloride), microcrystalline cellulose, ethyl alcohol, and three coating materials (HPMC, Eudragit L30D55, Eudragit FS30D) were eventually selected. Three kinds of coated pellets were mixed in capsules with the mass ratio of 1:1:1. The release curves of capsules were investigated in vitro under the simulated gastrointestinal conditions. In addition, the oral bioavailability and pharmacokinetics of VIN self-emulsifying pH gradient release pellets, commercial tablets and liquid VIN SEDDS were evaluated in Beagle dogs. The oral bioavailability of self-emulsifying pH gradient release pellets was about 149.8% of commercial VIN tablets, and it was about 86% of liquid VIN SEDDS, but there were no significant difference between liquid SEDDS and self-emulsifying pH gradient release pellets. In conclusion, the self-emulsifying pH gradient release pellets could significantly enhance the absorption of VIN and effectively achieve a pH gradient release. And the self-emulsifying pH gradient release pellet was a promising method to improve bioavailability of insoluble drugs.

In the present study, we select the Sylysia 350 (Sylysia) as mesoporous material, distearoylphosphatidylethanolamine-poly(ethylene glycol)2000 (DSPE-PEG) as absorption enhancer and hydroxy propyl methyl cellulose (HPMC) as crystallization inhibitor to prepare sorafenib tosylate (SFN) nanomitrix (MSNM@SFN) for improving the anti-tumor activity of SFN. The MSNM@SFN was prepared by solvent evaporation method. The solubility, dissolution, and bioavailability of SFN in MSNM@SFN were also investigated. The anti-tumor activity of MSNM@SFN was evaluated in vitro and in vivo. Our results indicated that the solubility and dissolution of SFN in MSNM@SFN were significantly increased. The oral bioavailability of SFN in MSNM@SFN was greatly improved 7.7-fold compared with that in SFN suspension. The enhanced anti-tumor activity of MSNM@SFN was confirmed in vitro and in vivo experiments. This nanomatrix developed in this study could be a promising drug delivery platform for improving the therapeutic efficacy of poorly water-soluble drugs.

Stable molecular clusters of ibuprofen and naproxen were prepared in dry ice, by supersonic jet expansion of their supercritical CO2 drug formulations into a liquid nitrogen cooled collection vessel, with up to 80% yield. Mixing the “dry ice” in water, resulted in the solubilization of the clusters and in the case of ibuprofen, we were able to create solutions, with concentrations of up to 6 mg/ml, a 300-fold increase over previously reported values. Drop casting and ambient drying of these solutions on silicon substrate resulted in a stable, viscous liquid film, referred to as nanostructured molecular liquids. These liquids exhibited a highly aligned, fine (self-assembled) super lattice features. In vitro cancer cell viability studies of these formulations exhibited similar cytotoxicity to that of the original raw materials, thus retaining their original potency. Besides its scientific importance, this invention is expected to open up new drug delivery platforms.

The aim of the study was to develop a novel buccal dosage form to transport rhodamine 123 and human insulin as models for poorly water-soluble and biological drugs, using lipid-core micelles (LCMs)-loaded mucoadhesive films. LCMs were synthesized by a low-energy hot emulsification process, yielding spherically shaped, small-sized, monodispersed and negatively charged carriers with high entrapment efficiency. In vitro release studies demonstrated a higher release of insulin rather than rhodamine from LCMs in simulated physiological conditions, due to an initial burst release effect; however, both release profiles are mainly explained by a diffusion mechanism. Furthermore, LCMs-loaded mucoadhesive films were manufactured and preserved with similar mechanical properties and optimal mucoadhesive behavior compared to nonloaded films. Ex vivo permeation experiments using excised porcine buccal epithelium reveal that both rhodamine and insulin-loaded LCM films elicited a significantly enhanced permeation effect compared to LCMs in suspension and free drugs in solution as controls. Hence, LCMs-loaded mucoadhesive films are suitable as buccal dosage form for the transport and delivery of rhodamine 123 and insulin, as models for poorly water-soluble and biological drugs, respectively.

We demonstrate the ability to fabricate dosage forms of a poorly water-soluble drug by using wet stirred media milling of a drug powder to produce an aqueous suspension of nanoparticles and then print it onto a porous biocompatible film. Contrary to conventional printing technologies, a deposited material is pulled out from the nozzle. This feature enables printing highly viscous materials with a precise control over the printed volume. Drug (griseofulvin) nanosuspensions prepared by wet media milling were printed onto porous hydroxypropyl methylcellulose films prepared by freeze-drying. The drug particles retained crystallinity and polymorphic form in the course of milling and printing. The versatility of this technique was demonstrated by printing the same amount of nanoparticles onto a film with droplets of different sizes. The mean drug content (0.19–3.80 mg) in the printed films was predicted by the number of droplets (5–100) and droplet volume (0.2–1.0 µL) (R2 = 0.9994, p-value < 10−4). Our results also suggest that for any targeted drug content, the number-volume of droplets could be modulated to achieve acceptable drug content uniformity. Analysis of the model-independent difference and similarity factors showed consistency of drug release profiles from films with a printed suspension. Zero-order kinetics described the griseofulvin release rate from 1.8% up to 82%. Overall, this study has successfully demonstrated that the electro-hydrodynamic drop-on-demand printing of an aqueous drug nanosuspension enables accurate and controllable drug dosing in porous polymer films, which exhibited acceptable content uniformity and reproducible drug release.

Amorphous solid dispersions (ASDs) improve the oral delivery of poorly water-soluble drugs. ASDs of olanzapine (OLZ), which have a high melting point and low solubility, are performed using a complicated process. Three-dimensional (3D) printing based on hot-melt pneumatic extrusion (HMPE) is a simplified method for producing ASDs. Unlike general 3D printing, printlet extrusion is possible without the preparation of drug-loaded filaments. By heating powder blends, direct fused deposition modeling (FDM) printing through a nozzle is possible, and this step produces ASDs of drugs. In this study, we developed orodispersible films (ODFs) loaded with OLZ as a poorly water-soluble drug. Various ratios of film-forming polymers and plasticizers were investigated to enhance the printability and optimize the printing temperature. Scanning electron microscopy (SEM) showed the surface morphology of the film for the optimization of the polymer carrier ratios. Differential scanning calorimetry (DSC) was used to evaluate thermal properties. Powder X-ray diffraction (PXRD) confirmed the physical form of the drug during printing. The 3D printed ODF formulations successfully loaded ASDs of OLZ using HMPE. Our ODFs showed fast disintegration patterns within 22 s, and rapidly dissolved and reached up to 88% dissolution within 5 min in the dissolution test. ODFs fabricated using HMPE in a single process of 3D printing increased the dissolution rates of the poorly water-soluble drug, which could be a suitable formulation for fast drug absorption. Moreover, this new technology showed prompt fabrication feasibility of various formulations and ASD formation of poorly water-soluble drugs as a single process. The immediate dissolution within a few minutes of ODFs with OLZ, an atypical antipsychotic, is preferred for drug compliance and administration convenience.

The intrinsic dissolution rate (IDR) of active pharmaceutical ingredients (API) is a key property that aids in early drug development, especially selecting formulation strategies to improve dissolution and thereby drug absorption in the intestine. Here, we developed a robust method for rapid, medium throughput screening of IDR and established the largest IDR dataset in open literature to date that can be used for pharmaceutical computational modeling. Eighteen compounds with diverse physicochemical properties were studied in both fasted and fed state simulated intestinal fluids. Dissolution profiles were measured in small-scale experimental assays using compound suspensions or discs. IDR measurements were not solely linked to API solubility in either dissolution media. Multivariate data analysis revealed that IDR strongly depends on compound partitioning into bile salt and phospholipid micelles in the simulated intestinal fluids, a process that in turn is governed by API lipophilicity, hydrophobicity, and ionization.

Co-amorphous systems have been proven to be a promising strategy to address the poor water solubility of poorly water-soluble drugs. Generally, the initial dissolution behaviors after co-amorphous system preparation and the potential recrystallization during storage are used to evaluate the performance of co-amorphous systems. However, this study reveals that decreased dissolution and unexpected increased dissolution were observed during storage though the co-amorphous systems maintained amorphous form. Three drugs (valsartan, tadalafil, mebendazole) and three co-formers (arginine, tryptophan, biotin) were used to prepare co-amorphous systems and the samples were stored for different times. After stored for 80 d, most of the co-amorphous systems maintained amorphous form, however, decreased and increased intrinsic dissolution rates (IDRs) were both observed in these non-recrystallized co-amorphous systems. The moisture changes of the systems during storage and the possible drug-co-former molecular interactions showed no effect on the dissolution changes, while phase separation might play a role in it. In conclusion, more attention should be paid to the dissolution changes of co-amorphous systems during storage. Focusing on the initial dissolution behaviors after sample preparation and the physical recrystallization during storage is not enough for the development of co-amorphous systems in future. [Display omitted] [ABSTRACT FROM AUTHOR]

Nanocrystals, a carrier-free colloidal delivery system in nano-sized range, is an interesting approach for poorly soluble drugs. Nanocrystals provide special features including enhancement of saturation solubility, dissolution velocity and adhesiveness to surface/cell membranes. Several strategies are applied for nanocrystals production including precipitation, milling, high pressure homogenization and combination methods such as NanoEdge™, SmartCrystal and Precipitation-lyophilization-homogenization (PLH) technology. For oral administration, many publications reported useful advantages of nanocrystals to improve in vivo performances i.e. pharmacokinetics, pharmacodynamics, safety and targeted delivery which were discussed in this review. Additionally, transformation of nanocrystals to final formulations and future trends of nanocrystals were also described.

Supercritical solvent impregnation (SSI) is a green unconventional technique for preparing amorphous drug formulations. A mesoporous nanostructured ZnO (mesoNsZnO) carrier with 8-nm pores, spherical-nanoparticle morphology, and an SSA of 75 m2/g has been synthesized and, for the first time, subjected to SSI with poorly water-soluble drugs. Ibuprofen (IBU), clotrimazole (CTZ), and hydrocortisone (HC) were selected as highly, moderately, and poorly CO2-soluble drugs. Powder X-ray diffraction, Fourier transform infrared spectroscopy, field emission scanning electron microscopy, nitrogen adsorption analysis, and ethanol extraction coupled with ultraviolet spectroscopy were employed to characterize the samples and quantify drug loading. Successful results were obtained with IBU and CTZ while HC loading was negligible, which could be related to different solubilities in CO2, drug size, and polarity. Successful SSI resulted in amorphous multilayer confinement of the drug. The mesoNsZnO-IBU system showed double drug loading than the mesoNsZnO-CTZ one, with a maximum uptake of 0.24 g/g. Variation of contact time during SSI of the mesoNsZnO-IBU system showed that drug loading triplicated between 3 and 8 h with an additional 30% increment between 8 h and 24 h. SSI did not affect the mesoNsZnO structure, and the presence of the adsorbed drug reduced the chemisorption of CO2 on the carrier surface.

Nanoconjugations have been demonstrated to be a dominant strategy for drug delivery and biomedical applications. In this review, we intend to describe several strategies for drug formulation, especially to improve the bioavailability of poorly water-soluble molecules for future application in the therapy of numerous diseases. The context of current studies will give readers an overview of the conjugation strategies for fabricating nanoparticles, which have expanded from conjugated materials to the surface conjugation of nanovehicles. Moreover, nanoconjugates for theranostics are also discussed and highlighted. Overall, these state-of-the-art conjugation methods and these techniques and applications for nanoparticulate systems of poorly water-soluble drugs will inspire scientists to explore and discover more productive techniques and methodologies for drug development.

The use of lipid-based formulations (LBFs) in improving the absorption of poorly water-soluble drugs has now well established. Because the in vivo evaluation of LBFs is labor-intensive, in vitro or ex vivo approaches could provide advantages. In this study, a new ex vivo lipolysis-absorption model (evLAM) composed of an intestinal digestion system and an intestinal tissue system was developed to evaluate and predict the in vivo absorption performances of LBFs. Model factors, including the pH of the system and concentrations of d-glucose and pancreatic lipase, were investigated and optimized by a Box-Behnken design. To evaluate this new model, a lipid formulation of indomethacin, which was chosen based on preliminary studies of pseudo-ternary phase diagrams, emulsion droplets, and solubility, was further investigated by an in vivo pharmacokinetic study of rats, the everted gut sac model, and the evLAM, respectively. The absorption percentages obtained from the evLAM were much more similar to the data of rats in vivo than those from the everted gut sac model, showing a preferable in vitro-in vivo correlation (r = 0.9772). Compared with the conventional in vitro and in vivo methods, the evLAM, which allowed precise insights into the in vivo absorption characteristics without much time or a complicated process, could be a better tool for assessing LBFs of poorly water-soluble drugs.

The present investigation deals with successful synthesis and surface functionalisation of mesoporous alumina (MeAl) nanoparticles by simplified sol–gel method using cetyl trimethyl ammonium bromide (CTAB) and pluronic as a template. Surface functionalisation of MeAl was performed to determine the selectivity of surface groups for coupling with model drug molecule. Repaglinide a BCS class II drug was loaded as a model drug on synthesised MeAl nanoparticle and studied for its sustained release capability. The synthesised and repaglinide loaded MeAl nanoparticles were characterised by Fourier transform infrared Spectroscopy, X‐ray diffraction, field emission scanning electron microscopy with EDAX, Transmission electron microscopy and differential scanning calorimetric. Results from the dissolution study confirmed the sustained release behaviour of the nanparticles which was up to 24 h. The cell viability assay demonstrated that 0.2 to 1 mg/ml concentration of MeAl was significantly less cytotoxic to the Chinese Hamster Ovary (CHO) cells. The authors' experimental studies suggest that MeAl can be used as drug carrier and have a potential to increase the stability, loading efficiency and patient compliance for poorly water‐soluble drugs such as repaglinide. [ABSTRACT FROM AUTHOR]

The aim of the project was to assemble two optimum solid lipid nanoparticle (SLN) formulations for oral delivery of loperamide (LPM) to treat different types of diarrhea, and to evaluate their release profiles in vitro and pharmacokinetic properties in vivo. In this work, glyceryl trimyristate (Dynasan 114) nanoparticles containing the drug LPM and sodium cholate as a stabilizer were prepared using a modified solvent evaporation technique. Two LPM-loaded SLNs, namely LPM-SLN-1 (LPM-SLN with a high ratio rate of lipid to drug) and LPM-SLN-2 (LPM-SLN with a low ratio rate of lipid to drug), were prepared by the solvent evaporation method. A change in the lipid concentration affects the characteristics of LPM-SLNs. The average sizes of the LPM-SLNs were 303 ± 18 nm and 519 ± 36 nm, separately, as analyzed by dynamic light scattering (DLS). The LPM-SLNs were found to be round with a smooth surface, as observed using a transmission electron microscope (TEM) and a scanning electron microscope (SEM). The average encapsulation efficiencies were 87 ± 3.78% w/w and 84 ± 5.17%, accordingly. In the in vitro release experiments, LPM-SLNs showed a continuous release profile of LPM without any burst release. The oral bioavailability of LPM-SLNs was analyzed using Wistar rats. The relative bioavailabilities of LPM-SLNs were 227% and 153%, respectively, as compared that of the LPM tablet. There was no difference in the Tmax between LPM-SLN-2 and the LPM tablet. In conclusion, LPM-SLN-1 significantly improved the oral bioavailability of LPM, while LPM-SLN-2 having the same swift action as the LPM tablet. These results demonstrate the potential of LPM-SLNs in the oral delivery of LPM to treat different types of diarrhea.